Obesity is a chronic disease with a high and rising prevalence, multiple physical and mental health complications, no cure, and an unknown etiology. Recent scientific work has identified multiple genetic causes of obesity in rodents, thus laying the foundation for unraveling the complex network of biologic pathways controlling body fat content. Paramount to identifying inherited factors producing human obesity is the acquisition of biologic samples from phenotypically well- characterized large populations with large numbers of nuclear families. The rapidly-advancing field of human genome analysis will provide improved technology for use in our study. Our hypothesis is that obesity is a heterogeneous disorder resulting from a combination of allelic differences in multiple genetic loci, some of which may be the human homologs of rodent obesity genes. We will continue our study entitled "The Genetic Epidemiology of Childhood Obesity" by carrying out these specific aims: 1) conduct a genome-wide search using multipoint linkage analysis and a candidate gene association study using TDT analysis by recruiting a new study population of previously-operated Bariatric Surgery patients and their family members through the International Bariatric Surgery Registry, and markedly obese children and adults from the University of Iowa Hospitals and Clinics and their family members; 2) screen for mutations in candidate genes for obesity by employing DNA, RNA from adipose tissue, and plasma leptin levels and binding properties; and 3) continue genetic analysis of the Muscatine, Iowa population by establishing genotypes at polymorphic loci within or near homologs of rodent obesity-genes, analyzing additional loci identified from a genome-wide search, and correlating these genotypes with phenotypic measures of body size and plasma leptin levels. By obtaining specimens from these large cohorts, we will also establish a bank of DNA, RNA and plasma for future study as the technology evolves.